1-substituted-3-substituted phenoxypyrrolidines

ABSTRACT

1-SUBSTITUTED-3-SUBSTITUTED PHENOXYPYRROLIDINES USEFUL AS ANTI-DEPRESSANTS ARE DISCLOSED. THE COMPOUNDS ARE PREPARED FROM 1-METHYL-3-PYRROLIDINOLS AND 1-BENZYL-3-PYRROLIDINOLS.

United States Patent Ofice Patented May 4, 1971 ABSTRACT OF THEDISCLOSURE 1-substituted-3-substituted phenoxypyrrolidines useful asanti-depressants are disclosed. The compounds are prepared froml-methyl-3-pyrrolidinols and 1-benzyl-3-pyrrolidinols.

The present invention relates to certain novel heterocyclic organiccompounds which may be referred to as 3- phenoxy-pyrrolidines and ismore particularly concerned with1substituted-3-substituted-phenoxypyrrolidines, compositions thereof,and methods of making and using the same The compounds of the presentinvention may be broadly represented by the following structuralformula:

,- L l R Formula I wherein;

R is :benzyl, methyl and carbamoyl,

R is carbamoyl, carboxy, aminocarbonyl, amino, benzamidomethyl,aminomethyl, hydroxymethyl, lower-alkoxy carbonyl, cyano, lower-alkylcarbonyl, acetamido, benzamido and carbamoyl amino, and

acid addition salts thereof.

The compounds of the invention represented by Formula I are generallycharacterized by important pharmacological activity. The activity isdemonstrable when the compounds are used in the form of the free base orin the form of their non-toxic acid addition salts. The preferred formof the compounds is as their non-toxic acid addition salts for increasedwater solubility and ease of administration.

Acid addition salts are prepared by reacting the selected base in theknown manner with an acidic component, typical mineral acids beinghydrohalic, phosphoric or sulfuric acid. Salts prepared using organicacids are within the purview of the invention, the preferred organicacids being maleic, fumaric, oxalic, tartaric and citric acid. l

The compounds of the invention are specifically useful in the field ofcomparative pharmacology. When the compounds are used and compared withother drugs as antiepressants by the method of Beryl M. Askew, LifeSciences, No. 10, pp. 725-730 (1963), they will demonstrate this actionbest when utilized at a dose (intraperitoneally in mice) within therange of about two to 50 mg./kg. and preferably at 2-20 mg./kg. Usingthe method of Askew, female mice were injected subcutaneously (s.c.)with 2 mg./kg. of reserpine in the late afternoon of the day precedingthe test. Approximately 18 hours later the temperature of the mice wasmeasured and groups of eight mice were injected intraperitoneally (i.p.)with the test drug or water. The temperature of the mice was measuredfour hours following the injection of the test drug or water. Theactivity of the compounds as antagonists of reserpine-inducedhypothermia was compared with the known antidepressant control drugdesmethylimipramine (DMI) and the results calculated as a percentage ofDMI response among the l-substituted-3-phenoxypyrrolidines tested. Thepreferred compounds are shown in Table I.

TABLE I Percent of DMI Dose and route response Example:

18 2mg./kg.i.p 56 27 2mg. g. i.p 45 20 rug/kg i. 77 28 2 mg/kg ip 49 30{2 rug/kg i 13 2O mg./kg l.p 35 48 20 rug/kg l.p 83

It is, therefore, an object of the present invention to provide novelcompounds having utility as anti-depressants. Another object is toprovide methods for producing the novel compounds and methods for theutilization thereof. Additional objects will become apparent hereinafterand still others will be apparent to one skilled in the art.

In the definition of the symbols in the formulas hereof and where theyappear elsewhere throughout this specification, the terms have thefollowing significance.

The term lower alkyl as used herein includes straight and branched chainradicals of from one to eight carbon atoms inclusive. Examples of loweralkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl,amyl, hexyl, heptyl, and octyl radicals.

The term carbamoyl as used herein includes not only the primarycarbamoyl group but also the secondary and tertiary carbamoyl groups aswell, including N-lower-alkyl carbamoyl, N-phenylcarbamoyl,N,N-diphenylcarbamoyl, N-cycloalkyl carbamoyl, N,N-di-lower-alkylcarbamoyl and the like.

Among the suitable amino radicals included within the symbol R areprimary, secondary and tertiary amino radicals, such as unsubstitutedamino (NH lower-alkylamino, di-lower-alkyl-amino, anilino, basicsaturated monocyclic heterocyclic radicals as exemplified :bymorpholino, pyrrolidino and piperidino.

The following Charts I and II illustrate the process of the inventionand show the various procedures involved in preparing the final productsof the invention. In Charts I and II, all the symbols have the valuespreviously assigned.

CHART I OH -OSO2P II (Note a) lnr (Note 0) CONH: F-Q

f R IV} Notes:

a. R is a benzyl or a methyl radical. b. P is an alkyl or an aryl group.

- CHART II r CH2 CoHs H Chart II illustrates the process of theinvention, whereby novel compounds within the scope of Formula I whereinR is a carbamoyl radical are prepared by hydrogenolysis of a l-benzyl 3phenoxypyrrolidine to a 3-phenoxypyrrolidine of Formula V, which is thenreacted with an isocyanate or a carbamoyl halide.

As shown in Chart I, a l-benzylor a 1-methyl-3- pyrrolidinol (II) isconverted to a l-benzylor l-methyl- 3-arylsulfonyloxypyrrolidine or a1-benzylor l-methyl- 3-alkylsulfonyloxypyrrolidine by reaction with anarylor alkylsulfonyl halide, and allowing the thus-formed3-sulfonyloxypyrrolidine to react with a phenol to produce a compound ofFormula IV, a compound within the scope of Formula I and the startingmaterial of the present invention.

As a general procedure for preparing the starting materials (IV), asuspension of sodamide in an appropriate solvent, e.g., dry toluene, isplaced in a suitable reaction vessel such as a three-necked,round-bottom flask provided with stirrer, reflux condenser, thermometerand dropping funnel. The stirred dispersion is maintained at atemperature below 50 0., generally between 25 C. and 45 C. during thedropwise addition of a l-substituted- 3-pyrrolidinol to the reactionmedium. A solution of an arylsulfonyl halide is then added to thereaction mixture while maintaining a reduced temperature, for example,about -l0 C. Arylsulfonyl halides such as otoluenesulfonyl chloride,p-toluenesulfonyl chloride and benzenesulfonyl chloride in toluenesolution may be employed in the formation of the desired sulfonates.Stirring of the reaction mixture is continued for an additional period,generally for about six hours while allowing the pot temperature to risegradually to ambient temperature. The reaction mixture is washed severaltimes with cold water and the washed toluene solution dried using asuitable drying agent as, for example, sodium sulfate. After removal ofthe drying agent, the dried toluene solution is concentrated underreduced pressure and the residual sulfonate allowed to react with aZ-carbamoylor 4-carbamoylphenol preferably in the form of the sodiumsalt in dimethylformamide. The sulfonate in dimethylformamide is addedto the solution of the phenol,

preferably as an alkali metal phenate, and the pot temperature raised toa level of about -120 C. for an extended period such as four to eighthours. On termination of the heating period the cooled reaction mixtureis partitioned between Water and a suitable organic solvent,illustratively ethyl acetate. The organic layer is separated andextracted with dilute mineral acid. The acid extracts are combined,basified with dilute aqueous base and the base-insoluble oil extractedwith an organic solvent. After drying over an inert drying agent, thesolvent is removed by evaporation and the residual l-substituted- 3-(2-or 4-carbamoylphenoxy)pyrrolidine is recrystallized from a suitablesolvent.

The following examples are given by way of illustration only and are notto be construed as limiting.

EXAMPLE 1 1-benzyl-3 (2-carb amoylphenoxy pyrrolidinel-benzyl-3-pyrrolidinol (19.3 g.; 0.11 mole) was added to a stirredsuspension of 4.3 g. (0.11 mole) of sodium amide in 60 ml. of drytoluene maintained at 35 C. After three hours at room temperature themixture was cooled to 20 C. and 19.0 g. (0.11 mole) of 2-toluenesulfonylchloride was added at a rapid rate, the pot temperature maintained at2030 C. After stirring two hours the mixture was allowed to standovernight at ambient temperature. The toluene solution was washed withwater, dried over sodium sulfate and concentrated. Thel-benzyl-S-pyrrolidinol 2-toluenesulfonate was added to adimethylformamide solution of 0.1 mole of the sodium salt ofsalicylamide prepared in ml. of dimethylformamide from 13.6 g. (0.1mole) of salicylamide and 5.4 g. (0.1 mole) of sodium methoxide. Thereaction mixture was refluxed five hours, cooled, partitioned betweenwater (500 ml.) and ethyl acetate (500 ml.). The ethyl acetate layer wasacid-base extracted and the base insoluble product crystallized fromisopropyl ether-ethyl acetate to give 12.5 g. (42%) of product whichmelted at l20.5122 C.

Analysis.-Calcd. for C H N O (percent): C, 72.95; H, 6.80; N, 9.46.Found (percent): C, 72.23; H, 6.78; N, 9.56.

EXAMPLE 2 1-benzyl-3- (4-carbamoylphenoxy) pyrrolidine EXAMPLE 31-benzy1-3-(2-morpholinylcarbonylphenoxy) pyrrolidine A solution of 30.0g. (0.10 mole) of 1-benzy1-3-(2- carboxyphenoxy)pyrrolidine (prepd. from1-benzyl-3-(2- carbamoylphenoxy)pyrrolidine using the procedure ofExample 28) in 100 ml. of thionyl chloride was refluxed one hour andconcentrated under reduced pressure. The residue was dissolved inchloroform and concentrated to remove gaseous by-products. A solution ofthe residue in 150 m1. of chloroform was treated dropwise with 100 ml.of morpholine with ice-bath cooling. After fifteen minutes stirring atroom temperature the chloroform solution was washed with dilute sodiumhydroxide solution. The chloroform layer was concentrated and theresidue distilled to give 19.0 g. (53%) of product; B.P. 235-238 C./0.1mm.

Analysis.--Calculated for C H N O (percent): C, 72.10; H, 7.15; N, 7.65.Found (percent): C, 71.74; H, 7.19; N, 7.76.

EXAMPLES 4-17 6 EXAMPLE 1-methyl-3-(Z-carbamoylphenoxy)pyrrolidine1-methyl-3-pyrrolidinol-2-toluenesulfonate was pre- The physicalconstants of additional examples of 1- pared as described in Example 1from 202 g. (2.0 moles) benzyl-3-phenoxypyrrolidines are given in TableI.

of l-methyl-3-pyrrolidinol, 85.6 g. (2.2 moles) of sodium TABLE I 7 CH2CgHs Analysis Calculated Found M P., B.P./ Example R 1 mm., C. C H N C HN 4 2-(CH3)2NCO 198/0. 1 74. 04 7. 46 8. 65 73. 56 7. 48 8. 82 52-CH2NHCO 210-20/0. 1 73. 52 7. 15 9. 03 73. 83 7. 46 9. 06 6 2(OH3)zNCHz 181/0. 07 77. 38 8. 44 9. 03 76. 90 8. 42 9. 05 2-NH2 180-5/0. 176. 08 7. 51 10. 44 7G. 38 7. 58 10. 44 2-CH2OH 180-8/0. 1 76. 29 7. 474. 94 76. 12 7. 46 4. 86 2-OH2NH) 175*80/0. 1 76. 56 7. 85 9. 92 76. 808. 05 9. 74 2-COOC2H 197-9/0. 1 73. 82 7. 12 4. 31 73. 34 6. 89 4. 362-CN 1846/(). 1 77. 67 6. 52 10. 07 77. 74 6. 61 10. 01 2-COOCH 185-8/0.1 73. 29 6. 80 4. 50 73. 02 6. 81 4. 65 2-C HgCO 181-5/0. 15 77. 26 7.17 4. 74 77. 01 7. 31 4. 88 4-CN 75. 5-77 77. 67 6. 52 10. 07 77. 45 6.52 10. 17 15 -CH2NCH2CH2O CHzCHz 189-94/0. 05 74. 96 8. 01 7. 95 75.208. 26 7. 75

16 1 4-COC3H7 1435 70. 08 7. 28 3. 89 70. 00 7. 4. 02 17 Z Z-CHsCONI-I139-41 64. 77 6. 15 6. 57 64. 82 6. 15 6. 67

1 Hydrochloride salt. 1 Maleate salt.

EXAMPLE 18 amide and 381 g. (2.0 moles) of 2-toluenesulfonyl chlo-3-(Z-carbamoylphenoxy)pyrrolidine hydrochloride An ethanol (150 ml.)solution containing 60 g. (0.2

ride. The sulfonate was reacted with 247 g. (2.0 moles) of salicylamideto yield 170 g. (38%) of product which melted at 116118 C.

111016) of Y m Y P Y)PYrrolidine Analysis.Calculated for C H N O(percent): C, and 52. of 10% pall catalyst was sh k 65.43; H, 7.32; N,12.72. Found (percent): C, 65.28; H, in three atmospheres of hydrogen at60 C. The reduced 7,23; N, 12 77 mixture Workup gave 34.5 g. (81.5%) ofoil, 13.1. 190-- AM 27 195 C./ 0.1 mm. The hydrochloride salt melted at155- 1 th 13 4 b 1 h 158 C. after recrystallization from methyl isobutylYP WPY ldllle kfitolle-isopfopalloll methyl-3-(4carbamoylphenoxy)pyrrolidine (M.P. Analysl'S-Ca1cu1atd for 11 15 2 2 (P200-202 C. from ethanol) was prepared in 68% yield C, 54.43; H, 6.23; N,11.54. Found (percent): C, 54.57; by the method f Example H, 6.33; N,11.47. Analysis-Calculated for C H N O (percent): C, EXAMPLE 19 65.43;H, 7.32; N, 12.72. Found (percent): C, 65.98; H,3-(2-morpho1inylcarbonylphenoxy)pyrrolidine N, 12.73-

oxarnate EXAMPLE 28 3-(2-morpholinylcarbonylphenoxy)pyrrolidine was preyYP Y)PY Olidille pared by hydrogenolysis of the l-benzyl precursor usingA O0 so1ut1on conta1n1ng 62.5 g. (1.55 moles) of sodium tllgesprgcedureof Example 18. The oxamate salt melted at g l fi 170A g. 7 mole) ofAMlysis-Ca1 =u1ated for 617112311306 (116mm C, $5 3.3322111131651331033037515625.3366Z1? Found (percent): 83; of the solutionadjusted to 7, filtered and the filtrate con- EXAMPLES 20 25 55centrated under reduced pressure. The residue was boiled withisopropanol, filtered and concentrated. The solid The physical constantsof additional examples of 3- residue was recrystallized fromisopropanol-water to phenoxy-pyrrolidines are given in Table II. yield16.0 g. of material which melted at 178-180 C.

TABLE II Analysis Calculated Found M P, B.1 Example R 1 mm. C. C H N G HN 200011 240 63.75 6.32 6.76 63.51 6. 24. 6.62 21 2 000311 133-5/0166.36 7.28 5. 95 66.57 7.27 6.05 216113 176-8 57.13 6.16 9. 52 57.136.13 9.13 2-OH3CONH 162-5 57.13 5.99 8.33 56.74 6.01 8.24 2-,4,5-CH;OC6H2)CONH 2524 53. 6.16 6.85 58.67 6.09 7. 04 25 4-CONH2 169'7164.06 6.84 13.60 64.24 6.83 13. 51

1 Fumarate salt. 2 Hydrochloride salt.

7 8 Analysis.Calculated for C H NO (percent): C, Analysis.-Calculatedfor C H N '0 (percent): C, 65.14; H, 6.83; N, 6.33. Found (percent): C,65.19; H, 65.99; H, 7.05; N, 7.00. Found (percent): C, 65.63; H, 6.84;N, 6.39. 7.01;N, 6.75.

EXAMPLE 29 EXAMPLES 31-47 l'methyl's"(z'aminophenoxy)Pyrrolidine 5 Thephysical constants of additional examples of 1- 1-methyl-3-pyrrolidinolbenzenesulfonate (33.8 g.; 0.14 methyl-3-phenoxypyrrolidines are givenin Table III.

TABLE 111 Analysis Calculated Found M.P.,B.P./ Example R mm.,C. o H N 0H N 87-9 68.11 6.03 3.99 68.39 6.14 4.02 "I l lgi lah 142-4/0.1 67.718.12 11.28 67.61 8.09 11.06 33 -2-OONOH2CH2OOH1CH2 180-4/01 66.18 7.649.66 66.17 7.60 9.61

166-7 64.06 6.87 6.79 63. 83 6.84 6.62 %-E8EIEQE%3O6HJ) 94-6 62.62 6.277.69 62.61 6.19 7.63 36 Z-NHCOCnHs 177-9 64.96 6.36 8.42 64.60 6.36 8.4137 2-NHGON(C@H5)2 222-6 66.93 6.09 8.16 66.03 6.09 8.06 38.. 2-OH2NH2116-20/. 06 69.87 8.79 13.68 69.84 9. 04 13.18 39 2-CH2NCH2CH2OCH2GH2143/. 06 69.63 8.76 10.14 69.19 8.77 10.02

1o3-7.06 71.76 9.46 11.96 71.46 9.69 11.62 iiIIIIIIIII 235%? 124-6i.1369.87 8. 79 13.58 70.19 8.96 18.23 4-0N 66-7 71.26 6.98 13.86 71.06 7.0013.88 40003111 120-3 61.62 7.92 4.78 61.69 7.76 6.122-NHOO(3,4,5-CH3OC6H2) 116-16 66.26 6. 78 7.26 66.46 6.86 7.19 2016121/01 71.25 6. 98 13.86 71.04 7.26 13.78 2.0003; 118/0 1 71.20 7.826.39 71.66 7.98 6.22 3 61.011. 186/30 76.05 9.33 6.82 76.87 9.18 6.78

1 Fumarate salt. 2 Hydrochloride salt. Hydrolodlde salt. mole) was addedto 150 ml. of dimethylformamide con- EXAMPLE 48 taining 7.8 g. (0.144mole) of sodium methoxlde and 15 1 [N cyclopentyl N (3trifluommethylphenyl)carbarm g. (0.138 mole) of 2-armnophenol. Afterfive hours at -3- 2. holinylcarbonylp e y)P 100 C. the cooled mixturewas partltioned between chloroform and water. The chloroform solutionwas acid- A Solutlon of gmole) of 3-(2- P base extracted and the baseinsoluble material crystallized 40 linylcarbonylpllenoxy) Pyrrolidine in20 of Pyridine from isooctane. The solid was sublimed at 90 c./0.1 wastreated Wlth 3- (01121 the product melted at N (3trifiuoromethylphenyl)-carbamoyl chloride. The A,lalysl-s. .ca1cu1atedfor CnHlsNzO (percent): C, mixture was stirred one hour, heated 0.5 houron a steam 68.71. H N Found (percent); 6843; H, bath, concentrated andthe residue partitioned between 842; 1 45 chloroform and dilutehydrochloric acid. From the chloro- EXAMPLE 30 51211110176138? 3.34 g.(30%) of product was obtamed; M.P.1-methyl-3-[4-(3,4,S-trimethoxybenzamidomethyl) Analysis.-Calculated forC H N- 04F (percent): C, phenoxyJpyrrolidine 63.26; H, 6.07; N, 7.91.Found (percent): C, 63.31; H, 6- To a solution of 19.5 g. (0.095 mole)of 1-methyl-3- 09 N 7 83 EXA L S (4-aminomethylphenoxy)pyrrolidine in100 m1. of chloro- MP E form was added dropwise a solution of 23.1 g.(0.1 mole) The physical constants of additional examples of 1- of3,4,5-trimethoxybenzoyl chloride in 75 ml. ofchlorocarbamoyl-3-phenoxypyrrolidines are given in Table IV.

TABLE IV R1 L J C(O)NR2R3 M.P. Analysis B.P./ Calculated Found ExampleR1 R2 R 6. o H N o H N 49 2-0 ONCHQCHZOCEZCHZ 0011. can". 189-98 71.326.20 8.91 71.04 6.18 8. 70

50 Same as above Same. CH3 134-44 67.46 6. 65 10.26 67.63 6. 72 10.27form. The mixture was stirred 0.5 hour, extracted with FORMULATIO AADMINISTRATION dilute sodium hydroxide solution and concentrated. Theresidue was crystallized from ethyl acetate-isopropyl ether. Usefulcompositions containing at least one of the com- The product weighed12.0 g. (32%) and melted at 131- pounds according to the invention inassociation with a 137 C. pharmaceutical carrier or excipient may beprepared in accordance with conventional technology and procedures.Thus, the compounds may be presented in a form suitable for oral orparenteral administration. For example, compositions for oraladministration can be solid or liquid and can take the form of capsules,tablets, coated tablets and suspensions, such compositions comprisingcarriers or excipients conveniently used in the pharmaceutical art.Suitable tableting excipients include lactose, potato, and maizestarches, talc, gelatin, and stearic, and silicic acids, magnesiumstearate, and polyvinyl pyrrolidone.

For parenteral administration, the carrier or excipient may be asterile, parenterally acceptable liquid; e.g., water or a parenterallyacceptable oil; e.g., arachis oil contained in ampules.

Advantageously, the compositions may be formulated as dosage units, eachunit being adapted to supply a fixed dose of active ingredients.Tablets, capsules, coated tablets and ampules are examples of preferreddosage unit forms according to the invention. Each dosage unit adaptedfor oral administration can conveniently contain to 100 mg. andpreferably to 50 mg. of the active ingredient, whereas each dosage unitadapted for intramuscular administration can conveniently contain 5 to100 mg. and preferably 10 to 25 mg. of the active ingredient.

The following formulations are representative for all of thepharmaceutically active compounds of the invention.

(1) Capsules: Capsules of 5, 25, and 50 mg. of active ingredient percapsule are prepared. With the higher amounts of active ingredients,reduction may be made in the amount of lactose.

Typical blend for encapsulation: Per capsule, mg.

Active ingredient 5.0 Lactose 296. Starch 129.0 Magnesium stearate 4.3

Total 435.0

(2) Tablets: A typical formulation for a tablet containing 5 mg. ofactive ingredient per tablet follows. The formulation may be used forother strengths of active ingredient by adjustment of 'weight ofdicalcium phosphate.

Per tablet, mg.

(1) Active ingredient 5.0 (2) Corn starch 13.6 (3) Corn starch (paste)3.4 (4) Lactose 79.2 (5) Dicalcium phosphate 68.2 (6) Calcium stearate0.9

Total 170.3

50 mg. tablet, ingredients: Per tablet, mg.

Active ingredient 50.0 Lactose 90.0 Milo starch 20.0 Corn starch 38.0Calcium stearate 2.0

Total 200.0

Uniformly blend the active ingredient, lactose, starches, and dicalciumphosphate when present. The blend is then granulated using Water as agranulating medium. The Wet granules are passed through an eight-meshscreen and dried at -l60 Fahrenheit overnight. The dried granules arepassed through a ten-mesh screen, blended with the proper amount ofcalcium stearate, and the lubricated granules then converted intotablets on a suitable tablet press.

(3) Injectable: 2% sterile solution.

Per cc.

Active ingredient 20 mg. Preservative, e.g., chlorobutanol 0.5% w./v.Water for injection, q.s.

Prepare solution, clarify by filtration, fill into vials, seal, andautoclave.

Various modifications in the compounds, compositions and methods of theinvention wil be apparent to one skilled in the art and may be madeWithout departing from the spirit or scope thereof, and it is thereforeto be understood that the invention is to be limited only by the scopeof the appended claims.

I claim:

1. A compound selected from (a) l-substituted 3substituted-phenoxypyrrolidines having the formula:

wherein;

R is selected from the group consisting of benzyl,

methyl and carbamoyl,

R is selected from the group consisting of carbamoyl, carboxy,aminocarbonyl wherein amino is primary amino, lower-alkylamino,di-loweralkylamino, morpholinyl, phenylamino andmtrifluoromethylphenylamino, primary amino,3,4,5-trimethoxybenzamidomethyl, aminomethyl rwherein amino is primaryamino, di-loweralkylamino and morpholinyl, hydroxymethyl, lower-alkoxycarbonyl, cyano, lower-alkyl carbonyl, acetamido, benzamido andcarbamoyl amino, and

(b) acid addition salts thereof.

2. A compound as defined in claim 1 wherein R is methyl and R isselected from the group consisting of carbamoyl, carboxy and3,4,S-trimethoxybenzamidomethyl.

3. A compound as defined in claim 2 wherein R is Z-carbamoyl.

4. A compound as defined in claim 2 wherein R} is 4-carbamoyl.

5. A compound as defined in claim 2 wherein R is 4- 3,4,5-trimethoxybenzamidomethyl) 6. A compound as defined in claim 1 whereinR is carbamoyl and R is aminocarbonyl wherein amino is primary amino,lower-alkylamino, di-lower-alkylamino,

v 12 morpholinyl, phenylamino and m-trifluoromethylphenyl- ReferencesCited ammo Wagner et a1.: Synthetic Organic Chemistry (1953),

7. A compound as defined in claim 6 wherein R is 2 647 65 822 23N,N-dipheny1carba-moyl. 2 8 6 8. A compound as defined in claim 6wherein R is 5 ALEX MAZEL, Primary ExaminerNcyclopentyl-N-(3-trifluoromethy1pheny1)carbamoyl.

9. A compound as defined in claim 8 wherein R is NARCAVAGE, AsslstantExammer morpholinocarbonyl.

10. A compound as defined in claim 9 wherein R is 2-mo1'pholinocarbonyl.10 260--326.3, 326.5; 424248, 274-

